PHA/ATS Partnership Grant Winner 2006

Xinqi Wu, PhD

Children’s Hospital Boston
“Hypoxic regulation of BMP signaling and the role of Id1 in the development of pulmonary hypertension”
Term: January 1, 2006 – December 31, 2007

Summary of Research Project:

Hypoxic regulation of BMP signaling and the role of Id1 in the development of pulmonary hypertension

Primary pulmonary hypertension (PPH) is a fatal disorder characterized by excessive growth of blood vessel cells in the lungs, resulting in narrowing of vessels and increased blood pressure in the lungs followed by heart failure. Genetic studies have linked PPH to heterozygous mutations in the type 2 bone morphogenetic protein receptor (BMPR) gene. These mutations could cause disruption of BMPR signaling, resulting in increased growth and inhibition of apoptosis of vascular cells. A second hit is also required for the disease to be manifested. Hypoxia is a particularly important stimulus for pulmonary hypertension (PH) and has been used in several animal models to understand the pathogenesis of this disease. The molecular mechanisms for PPH and hypoxia-induced PH remain poorly understood. We found that hypoxia suppressed BMPR signaling in cultured human pulmonary artery smooth muscle cells (HPASMC), resulting in suppression of BMP-stimulated Id1 gene activation. Id1 attenuated proliferation and promoted apoptosis of HPASMC. Thus, we hypothesize that the suppression of Id1 may cause increased growth and inhibition of apoptosis of HPASMC, significantly contributing to PH development. We proposed to investigate Id1 expression in hypoxic lungs of mice and the role of Id1 in cell cycle progression, proliferation, apoptosis and migration, processes underlying vascular remodeling. We will identify additional hypoxia-regulated BMP target genes. These studies will enhance our understanding of PPH pathogenesis and may lead to the identification of molecules that play a critical role in PPH development and thus might be used as targets for therapeutic intervention.

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